CARDIAC ISSUES

Although breast cancer is the most feared disease by most women in the US, it is far from the leading cause of death in women.21,22 CVD is the number 1 killer of women, claiming well over 400,000 lives each year. Sadly, nearly 50% of women are unaware that heart disease is the leading cause of death among women.23 Survival of patients with breast cancer has dramatically increased in the last 2 decades, largely owing to earlier detection by advanced mammographic screening technologies, increased patient awareness, and of course more effective treatment modalities.24 This success, however, may lead to an unintended increase in the incidence of mortality due to CVD. Although each year many women succumb to CVD, the risk of death due to CVD may be greatly increased in survivors of breast cancer by the addition of adjuvant therapies, regardless of cancer stage, at the time of diagnosis.

A further concern, demanding urgent attention, is that the rate of younger women (aged 35 to 44 years) who develop CVD is on the rise.25,26 Overlapping with this age group are the younger and younger women receiving a diagnosis of breast cancer. Therefore, the diagnosis, treatment, and long-term sequelae of treatment may be converging on patients who are currently facing a breast cancer diagnosis and are thus subjected to “modern” protocols. As with the treatment of other malignancies occurring at young ages (eg, Hodgkin disease), the long-term sequelae of breast cancer treatment are just now, decades later, becoming fully realized. In fact, a subset of cardiologists in the US and internationally is focusing on a new subspecialty—cardio-oncology—a specialty in managing the long-term cardiovascular side effects of the treatment of malignancies.27 Many survivors of breast cancer are at significantly increased risk of death caused by CVD, far exceeding their risk of death resulting from the initial cancer itself or from a recurrent cancer.21,22,28,29

Chemotherapy

The development of multiple antineoplastic agents—many novel but also many older (decades old)—has dramatically increased breast cancer OS. Unfortunately, many of the chemotherapeutic agents used have the potential to cause cardiovascular complications, some acute but most chronic.30,31 The spectrum of CVD in the setting of breast cancer therapy includes congestive heart failure (CHF), myocardial ischemia, hypertension, arrhythmias, QT prolongation, bradycardia, pericarditis, acute coronary syndrome, and thromboembolic events (TEs).31-34

Anthracyclines: Doxorubicin and Epirubicin: Anthracyclines bind to the DNA of malignant cells, interfering with the replication process and resulting in cellular death. Anthracycline therapy has been shown to increase the development of CHF and cardiomyopathy by 2%,34-39 doubling to 4% if used in conjunction or sequence with trastuzumab.34,39-43

Of particular importance to the primary care physician, extensive data are available in the literature about the potential long-term sequelae of the cardiotoxicity of anthracycline-based therapy for survivors of breast cancer.31-34 Furthermore, it should be noted that anthracycline therapy may not result in cardiotoxicity, particularly CHF, which is clinically evident for 10 to 20 years after treatment.33,44,45

Alkylating Agents: Cyclophosphamide: Alkylating agents act by reacting with the proteins of the DNA of cancer cells by adding an alkyl group to them. This disrupts effective DNA replication, resulting in the apoptosis of cancerous cells. Cyclophosphamide therapy can lead to cardiac damage, resulting in heart failure in nearly 30% of patients receiving the drug.46-48

As with most chemotherapeutic agents, the risk of cardiotoxicity appears to be dose related.33,47 In addition to dose, prior anthracycline therapy, a history of mediastinal radiation, and elderly age are further risk factors for cardiotoxicity.29,45-47,49,50

Cytoskeletal Disruptors (Taxanes): Paclitaxel and Docetaxel: Cytoskeletal disruptors inhibit the process of cell division through the interruption of microtubular functions, which are essential for cell division. Taxanes have been incorporated in the treatment of breast cancer only since the 1990s and, as such, their long-term cardiotoxic side effects may not yet have been adequately identified and reported. Furthermore, the multiple-combination chemotherapies used, which have included the addition of a taxane-based agent, make it difficult to decipher the true incidence of cardiotoxicity attributable to these drugs, particularly when administered alone.29,45,51-54

Although the most common side effects of taxane therapies are related to arrhythmias, particularly bradycardia, myocardial ischemia has also been reported. The incidence with paclitaxel use is 0.5% to 5% and with docetaxel appears to approach 2%.33 CHF resulting from docetaxel has ranged from 2.3% to 8%.51,55 It should be noted that most data for the development of cardiotoxicity has accumulated from the use of paclitaxel.56

As noted previously, the cardiotoxicity of systemic therapies may become one of the most devastating consequences of the treatment itself, particularly when an additional comorbidity such as a history of coronary artery disease, hypertension, or smoking is added to the patient’s active problem list (Table 1).45,56-58

Radiation Therapy

The current standard of care for the treatment of early-stage breast cancer involves giving a patient an informed choice regarding surgical options.59-61 The effectiveness of breast-conserving therapy (BCT), beginning in the 1970s with quadrantectomy vs mastectomy, has been fully verified with numerous studies, some reporting more than 2 decades of follow-up data.62-67 These findings have resulted in BCT as the primary surgical option for most patients during the past 2 decades. An integral part of BCT is the mandatory addition of adjuvant radiation therapy (RT).63,64,68 This surge in BCT has resulted in a large number of patients who receive adjuvant RT for early-stage breast cancer; rates of recurrence and death are markedly reduced.69-75

Cardiac injury resulting from RT to the thorax has long been recognized. Because of the increasing number of patients who have become long-term survivors of breast cancer thanks to BCT and RT, attention has now been directed to the late side effects of RT. These include direct damage to the myocardium and the coronary arteries, resulting in an increase in CHF and myocardial infarction compared with patients who do not receive RT.29,33,76

Since the mid-1980s, the mean centigray cardiac exposure has decreased because of improved technologies, such as computed tomography for simulation for RT; nonetheless, even small amounts of radiation reaching the heart may be damaging.77-82 It is estimated that each centigray exposure the heart receives increases the risk of death due to heart disease by 3%.83,84 The incidence and severity of cardiac morbidity and mortality risk are far greater for left-sided disease by virtue of human anatomy.81,85-88

As with chemotherapy, the risk of death due to RT starts to rise 10 years after treatment and may not be fully manifest until the second decade after therapy.83,88 RT has a long-term effect; therefore, it is important to be cognizant of the lengthy delay in cardiac symptoms, particularly as the patient ages and becomes more vulnerable to the development of CVD.89 Because RT has evolved over the years, incorporating new technologies, administration schedules, and delivery of centigray doses, the side effects for contemporary patients may be somewhat lessened, although long-term follow-up is not yet available.76,90-94

Hormonal Blockade

Tamoxifen:Tamoxifen is a selective estrogen receptor modulator (SERM) and inhibits the growth of breast cancer cells by its antiestrogenic activity through its competitive inhibition of estrogen binding to estrogen receptors.95,96 Since its introduction in the 1970s, tamoxifen has been shown to reduce the risk of breast cancer recurrence and mortality by more than 30%.97,98 Tamoxifen has been heralded as one of the most important advances in the treatment of breast cancer because approximately 70% of these patients have estrogen receptor-positive (ER+) cancer.99-103

The side effects of tamoxifen therapy are typically those that accompany the onset of menopause. These include hot flashes, mood swings, depression, loss of libido, and vaginal dryness.101 In addition, tamoxifen increases the risk of thromboembolic complications, including deep venous thrombosis, pulmonary embolism (PE), and cerebral vascular events.104-107 Tamoxifen has also been associated with an increase in the development of endometrial cancer97,105; therefore, women receiving this form of hormonal blockade who experience spotting require urgent gynecologic referral for uterine biopsy to rule out cancer. Because tamoxifen is a SERM, a beneficial effect is an apparent decrease in the incidence of myocardial infarction and CVD-related death as well as offering protection from osteoporosis and fracture risk in postmenopausal patients.106-108

A final but important consideration for patients receiving tamoxifen therapy centers on the recognized interactions with this drug in two common comorbid conditions: coagulation and depression. An aging population results in an increasing incidence of cardiac arrhythmias and other conditions resulting in the need for long-term anticoagulative therapy. Tamoxifen potentiates the action of warfarin by competing with its metabolizing enzyme, cytochrome P4503A4, which may result in major hemorrhagic consequences.103,109

Antidepressants are one of the most commonly prescribed medications in the US.110-112 Commonly prescribed antidepressants classified as selective serotonin reuptake inhibitors (SSRIs) inhibit the enzyme CYP2D6 and thus may slow the metabolism of tamoxifen, resulting in a decrease of its potency and thereby increasing the risk of recurrence.113-116

Aromatase Inhibitors: Letrozole, Anastrozole, and Exemestane:Aromatase inhibitors (AIs) work by blocking the enzyme aromatase, which converts adrenal androgens into estrogens. Whereas tamoxifen is employed in premenopausal women who have ER+ tumors, AIs are the estrogen blocker of choice in postmenopausal women whose cancer is ER+. AIs have been established as an effective adjuvant treatment in the postmenopausal group.101,117-119 In women, AIs have similar side effects to tamoxifen regarding menopausal symptoms (eg, hot flashes, mood swings, vaginal dryness, and loss of libido).97,101-120 The risk of CVD, including myocardial infarction, CHF, hypertension, and hyperlipidemia, remains controversial because published studies have failed to adequately resolve these issues.106-108,121-126 Until more definitive data are available, it would be prudent to err on the side of caution and consider those patients who are also receiving long-term AI therapy to be at an increased risk for the development of CVD.

Although arthralgias are an important side effect of AI therapy,101,122,123 a potentially more clinically important side effect is the development of bone loss. Osteopenia (a decrease in bone calcium content) and osteoporosis (a decrease in the actual bony matrix) are well-recognized side effects of AI therapy.127 Further discussion of bone loss are addressed in the section, Bone Health.

Targeted Biologic Therapies: Trastuzumab and Lapatinib

Targeted biologic agents are directed at protein kinases and the receptors that activate them. Approximately 15% to 30% of all breast cancers are human epidermal growth factor receptor 2-positive (HER2+) and, as such, the HER2 receptor tyrosine kinase pathway has become an important therapeutic target.128-134 The main function of the HER2/neu oncogene (now also called ERBB2) is to promote the differentiation, growth, and survival of cells, thereby enhancing the aggressiveness of these breast cancers, resulting in an overall outcome that is inferior to those patients not overexpressing this oncogene.135-139 Multiple studies have demonstrated a reduction in mortality and an increase in OS in HER2+ patients when trastuzumab has been incorporated into their treatment regimens.140-142 When used as a single treatment agent, trastuzumab increases the duration of survival, which is augmented by the administration of additional chemotherapeutic agents.128,138,143 The most severe complication of trastuzumab therapy has been its potential to adversely affect cardiac function; however, the exact mechanism of its cardiotoxicity remains unclear.31,144

The risk of trastuzumab-related cardiac events, as with other cardiotoxic agents, increases when additional CVD risk factors are noted, especially a history of coronary artery disease or impaired left ventricular dysfunction.56,145 On a positive note, it appears that the cardiotoxic effects of trastuzumab are reversible as long as they are identified early through rigorous monitoring during administration.29,145-149

Lapatinib, an orally administered medication, appears to be associated with a lower incidence of cardiotoxicity compared with trastuzumab.150 It appears that the cardiotoxicity associated with lapatinib is not as severe and is also reversible.151 Lapatinib is a new targeted modality, and further clinical investigation is needed before definitive conclusions about its cardiac safety are made, especially in light of the fact that many treatment options employed in breast cancer therapy have been demonstrated to have delayed long-term toxicities. In addition, further follow-up studies need to be conducted to determine whether outcomes are comparable to those of trastuzumab therapy.146,152,153

The cardiovascular complications of breast cancer treatment are an extremely complex subject, involving numerous variables that may be difficult to isolate. The multifocal approach to treatment includes many chemotherapeutic agents, alone and/or in combination, as well as RT modalities, options for hormonal blockade depending on menopausal status, and targeted therapies. Dosages, sequence of administration, and concordant or tangential approaches further complicate a thorough understanding of both the short-term and long-term toxicity of the administered therapies. The cluster of therapies such as anthracycline-based chemotherapy, right- or left-sided RT, trastuzumab administration, and hormonal blockade with AIs may contribute to an increased incidence of CVD.39-48,62,67,153-156 In particular, there have been recent concerns calling for further investigation of targeted therapies used in combination with RT and the potential for long-term cardiovascular side effects.92,147,154,157 Table 1 summarizes the potential long-term cardiovascular side effects of chemotherapy.

Further complicating the multiple cardiotoxicities of breast cancer therapy are the long, well-recognized, preexisting conditions that predispose to CVD (obesity, hypertension, dyslipidemias, and DM). Patients with breast cancer, most of whom now are becoming long-term survivors, may harbor one or more of these comorbidities, all of which increase as the population ages. Because of the complexity of the long-term side effects of treatment modalities for breast cancer, those addressing survivorship care must be aware of the need to incorporate a multidisciplinary approach to issues surrounding assessment and management of CVD, which remains the leading cause of mortality in women.158 Lifestyle changes that address these concerns are discussed in greater detail in the section, Lifestyle Management and Breast Cancer.

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